Avandia's Heart Risk Higher Than Others in Its Class

MONDAY Nov. 24, 2008 -- The widely used diabetes drug Avandia -- already controversial because of cardiovascular side effects -- may be riskier than Actos, another drug in the same class, researchers reported Monday.

The risk of heart failure and death for older diabetics appears greater with Avandia (rosiglitazone) than with Actos (pioglitazone), both of which are part of a class of drugs called thiazolidinediones, Harvard University researchers said.

Avandia and Actos are used to lower blood sugar in patients with type 2 diabetes. Recent studies suggested that the risk for heart failure, death and heart attack were increased with Avandia, touching off a controversy that resulted in new FDA-mandated label warnings about the drug.

"By contrast, Actos did not appear to increase the risk of cardiac events," said lead researcher Dr. Wolfgang C. Winkelmayer, an assistant professor of medicine at Harvard Medical School. "One could get the impression that Actos led to the reduction of heart attacks."

Indirectly, people inferred that it might be better to use Actos, because Avandia has cardiovascular risks associated with it, Winkelmayer said.

"We did find that patients using rosiglitazone actually had an increased risk of mortality from any cause. We did not find a difference in heart attacks and strokes," Winkelmayer said. But, he added, more patients taking Avandia were hospitalized for heart failure.

Winkelmayer noted differences in drugs in the same class are not unusual. For example, cholesterol-lowering statins (which include Crestor, Lipitor and Zocor) have different side effects, he said.

The new research, published in the Nov. 24 issue of the Archives of Internal Medicine, received funding from the American Heart Association, as well drug makers Amgen and GlaxoSmithKline, which makes Avandia.

For the study, Winkelmayer's team collected data on more than 28,000 diabetic patients aged 65 and older who were taking Avandia or Actos between 2000 and 2005. Among these patients, 50.3 percent took Actos and 49.7 percent took Avandia.

After a little more than a year on the medications, 1,869 patients died. The researchers found that patients taking Avandia had a 15 percent higher rate of death compared with patients taking Actos. In addition, Avandia patients had a 13 percent greater risk of heart failure than patients on Actos.

GlaxoSmithKline defended its drug in a statement on the new research released Monday.

The company "strongly supports the safety and efficacy of Avandia based on extensive clinical trial experience and widespread post-marketing use. This new study is inconsistent with evidence from randomized clinical trials and has significant limitations," the statement said.

A randomized clinical trial -- in which participants are randomly grouped and then followed prospectively over time -- is typically considered more reliable than an observational study, which is not as well-controlled.

"The primary outcome in this observational analysis is all-cause mortality," the company statement added. "The Avandia prescribing information includes data from RECORD, an ongoing long-term randomized clinical trial that has shown no statistically significant differences between the Avandia group and the control group regarding death from cardiovascular causes or any cause."

The continuing controversy over the heart risks of these diabetes drugs began with a 2007 study, published in the New England Journal of Medicine, in which heart expert Dr. Steven E. Nissen, chairman of the Cleveland Clinic's department of cardiovascular medicine, reported a 43 percent increased risk of heart attack among patients taking Avandia.

In November 2007, the U.S. Food and Drug Administration said that GlaxoSmithKline had agreed to add to the existing "black box" a new warning about the potential increased risk for heart attacks. Previously, the FDA had requested that GlaxoSmithKline and Takeda Pharmaceuticals, the maker of Actos, add a "black box" warning about the increased risk of heart failure associated with both drugs.

In July 2008, an FDA advisory panel said that drugs designed to control type 2 diabetes, including Avandia, should be subjected to more thorough safety reviews to ensure they don't raise the risk of heart problems. They recommended that all makers of these drugs conduct long-term cardiovascular trials, even if the drugs show no signs of heart problems in initial trials.

But Winkelmayer believes that neither Avandia nor Actos should be used as initial treatment. When they are used, they should be used with caution, especially with patients prone to heart problems, he said.

Dr. Eric J. Topol, director of the Scripps Translational Science Institute and chief academic officer at Scripps Health in La Jolla, Calif., also thinks both drugs should be used cautiously.

"The study reinforces the heart failure risk of rosiglitazone versus pioglitazone," Topol said. "Interestingly, it doesn't show any difference in heart attack, which is the one issue that has been so controversial. So it doesn't really change things that much."

Of the two drugs, Actos appears to have a more favorable track record, Topol added. "But the possibility of cardiovascular side effects, including heart failure and heart attack, can't be forgotten."

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